N-methyl-D-aspartate receptor (NMDAR) activation can result in both long and short-term plasticity, promote cell survival, initiate cell death, and is also critical for normal synaptogenesis during development. A number of studies suggest that the consequences of NMDAR activation can vary widely depending on receptor localization, temporal characteristics, and size of the signal (Bito et al., 1996; Fields et al., 1997; Hardingham et al., 1999; Chawla and Bading, 2001; Hardingham et al., 2001a, b). The focus of this study is the physiological role of extrasynaptic vs. synaptic NMDARs. Cultured neuron studies have suggested that NMDARs can exist as synaptic NR1/NR2A heteromers and extrasynaptic NR1/NR2B heteromers. These two receptor types may be coupled to very different cellular processes, with calcium entry through extrasynaptic NMDARs activating cell death mechanisms and LTD rather than LTP (Lu et al., 2001; Hardingham et al., 2002). Although these experiments have provided valuable clues about possible spatial and functional segregation of extrasynaptic NMDARs in neurons, the existence and physiological relevance of these receptors in intact tissue remains unclear. Our preliminary results, which are significantly different from culture measurements, suggest that approximately 40% of the NMDAR population is extrasynaptic in acute hippocampal slice dendrites. This indicates that there is a large pool of extrasynaptic receptors available for activation during periods of high presynaptic activity. Our underlying hypothesis is that extrasynaptic NMDARs participate in neuronal interactions under pathological and physiologically relevant conditions. This hypothesis will be tested by determining the size of the extrasynaptic NMDAR pool, subunit composition, and developmental expression in acute hippocampal brain slices. We will determine the conditions under which extrasynaptic receptors can participate in transmission and their role in the expression of long-term potentiation or depression. [unreadable] [unreadable]